Immune checkpoint inhibitors (ICI) transformed the treatment landscape of hepatocellular carcinoma (HCC). Unfortunately, patients with attenuated MHC-I expression remain refractory to ICIs, and druggable targets for upregulating MHC-I are limited. Here, we found that genetic or pharmacologic inhibition of fatty acid synthase (FASN) increased MHC-I levels in HCC cells, promoting antigen presentation and stimulating antigen-specific CD8+ T-cell cytotoxicity. Mechanistically, FASN inhibition reduced palmitoylation of MHC-I that led to its lysosomal degradation. The palmitoyltransferase DHHC3 directly bound MHC-I and negatively regulated MHC-I protein levels. In an orthotopic HCC mouse model, Fasn deficiency enhanced MHC-I levels and promoted cancer cell killing by tumor-infiltrating CD8+ T cells. Moreover, the combination of two different FASN inhibitors, orlistat and TVB-2640, with anti–PD-L1 antibody robustly suppressed tumor growth in vivo. Multiplex IHC of human HCC samples and bioinformatic analysis of The Cancer Genome Atlas data further illustrated that lower expression of FASN was correlated with a higher percentage of cytotoxic CD8+ T cells. The identification of FASN as a negative regulator of MHC-I provides the rationale for combining FASN inhibitors and immunotherapy for treating HCC. Significance: Inhibition of FASN increases MHC-I protein levels by suppressing its palmitoylation and lysosomal degradation, which stimulates immune activity against hepatocellular carcinoma and enhances the efficacy of immune checkpoint inhibition.

Hepatitis B virus (HBV) infection is associated with hepatitis and hepatocellular carcinoma (HCC). Considering that most HBV-infected individuals remain asymptomatic, the mechanism linking HBV to hepatitis and HCC remains uncertain. Herein, we demonstrate that HBV alone does not cause liver inflammation or cancer. Instead, HBV alters the chronic inflammation induced by chemical carcinogens to promote liver carcinogenesis. Long-term HBV genome expression in mouse liver increases liver inflammation and cancer propensity caused by a carcinogen, diethylnitrosamine (DEN). HBV plus DEN-activated interleukin-33 (IL-33)/regulatory T cell axis is required for liver carcinogenesis. Pitavastatin, an IL-33 inhibitor, suppresses HBV plus DEN-induced liver cancer. IL-33 is markedly elevated in HBV⁺ hepatitis patients, and pitavastatin use significantly correlates with reduced risk of hepatitis and its associated HCC in patients. Collectively, our findings reveal that environmental carcinogens are the link between HBV and HCC risk, creating a window of opportunity for cancer prevention in HBV carriers.

Background/Objectives: Chronic inflammation is a key driver of cancer. Interleukin 33 (IL-33) has emerged as a crucial factor involved in the pathogenesis of cancer-prone chronic inflammation. IL-33 functions as a cytokine and a nuclear protein to initiate chronic inflammation and cancer. However, small molecules capable of suppressing IL-33 expression to block its cytokine and nuclear functions are underexplored. Methods: The impact of tropisetron on IL-33 expression and its role in suppressing pancreatitis and pancreatitis-mediated pancreatic cancer were examined. Results: We demonstrate that tropisetron suppresses IL-33 expression, with high potential to serve as a novel therapeutic strategy for preventing chronic inflammation and its cancer sequela. Through screening 1018 Food and Drug Administration (FDA)-approved drugs, we discovered that tropisetron, a 5-hydroxytryptamine type 3 (5-HT3) antagonist commonly used to prevent and treat nausea and vomiting, effectively blocked IL-33 expression by suppressing IRF3 activation. Tropisetron inhibited pancreatitis and its progression to pancreatic cancer in mice. Conclusions: Tropisetron is an IL-33 inhibitor and can provide a novel therapeutic strategy to prevent and treat chronic pancreatitis and its associated cancer.

Immune checkpoint inhibitors (ICI) transformed the treatment landscape of hepatocellular carcinoma (HCC). Unfortunately, patients with attenuated MHC-I expression remain refractory to ICIs, and druggable targets for upregulating MHC-I are limited. Here, we found that genetic or pharmacologic inhibition of fatty acid synthase (FASN) increased MHC-I levels in HCC cells, promoting antigen presentation and stimulating antigen-specific CD8+ T-cell cytotoxicity. Mechanistically, FASN inhibition reduced palmitoylation of MHC-I that led to its lysosomal degradation. The palmitoyltransferase DHHC3 directly bound MHC-I and negatively regulated MHC-I protein levels. In an orthotopic HCC mouse model, Fasn deficiency enhanced MHC-I levels and promoted cancer cell killing by tumor-infiltrating CD8+ T cells. Moreover, the combination of two different FASN inhibitors, orlistat and TVB-2640, with anti–PD-L1 antibody robustly suppressed tumor growth in vivo. Multiplex IHC of human HCC samples and bioinformatic analysis of The Cancer Genome Atlas data further illustrated that lower expression of FASN was correlated with a higher percentage of cytotoxic CD8+ T cells. The identification of FASN as a negative regulator of MHC-I provides the rationale for combining FASN inhibitors and immunotherapy for treating HCC.Significance:Inhibition of FASN increases MHC-I protein levels by suppressing its palmitoylation and lysosomal degradation, which stimulates immune activity against hepatocellular carcinoma and enhances the efficacy of immune checkpoint inhibition.